Controlled release pharmaceutical compositions of carbidopa and levodopa

ABSTRACT

The present invention relates to controlled release pharmaceutical compositions of carbidopa and levodopa that include a combination of different molecular weight cellulose ethers and in particular, hydroxypropyl cellulose ether.

FIELD OF THE INVENTION

The present invention relates to controlled release pharmaceuticalcompositions of carbidopa and levodopa that include a combination ofdifferent molecular weight cellulose ethers and in particular,hydroxypropyl cellulose ether.

BACKGROUND OF THE INVENTION

Controlled drug delivery includes both sustained and extended deliveryand targeted delivery on a one time or sustained basis. Controlledrelease formulations can be used to reduce the amount of drug necessaryto cause the same therapeutic effect in patients. The convenience offewer, but more effective doses, also increases patient compliance.

Parkinson's disease is associated with the depletion of dopamine fromcells in the corpus striatum. Dopamine does not cross the blood-brainbarrier and cannot, therefore, be delivered in that form to treatParkinson's disease. Its immediate precursor, levodopa, is administeredinstead because it penetrates into the brain through the blood-brainbarrier where it is decarboxylated to dopamine. Levodopa, however, alsois decarboxylated to dopamine in peripheral tissues and consequentlyonly a small portion of administered levodopa is transported unchangedto the brain. The decarboxylation reaction can be blocked by carbidopa,which inhibits decarboxylation of peripheral levodopa but cannot itselfcross the blood-brain barrier and hence has no effect on the metabolismof levodopa in the brain.

The combination of carbidopa and levodopa is considered to be the mosteffective treatment for symptoms of Parkinson's disease. However, aftertaking carbidopa/levodopa immediate-release formulations for severalyears, some patients find that the effect of the medication begins towear off well before the scheduled time for administration of the nextdose. Various responses to this problem have been proposed, e.g.,shorten the intervals between immediate-release doses (or add anadditional dose if needed); switch from immediate-release to controlledrelease carbidopa/levodopa formulations.

Because of the disadvantages of increasing dose frequency and amount,leading to reduced patient compliance, a number of research endeavorshave been directed towards preparing controlled release formulations ofcarbidopa and levodopa.

For example, U.S. Pat. No. 4,424,235 discloses hydrodynamically balancedcontrolled release formulations containing both L-Dopa and adecarboxylase inhibitor. The capsules and tablets are hydrodynamicallybalanced to have a bulk density (specific gravity) of less than 1 and,therefore, remain floating in gastric fluid, which has a specificgravity of between 1.004 and 1.010. The controlled release formulationsare described as including a mixture of the active ingredients with asingle polymer selected from a natural gum, methylcellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodiumcarboxymethyl cellulose. The formulations further contain fattymaterials to make the drug float in the stomach, where the polymervehicle releases the drug. The dosage form remains buoyant and freelyfloating in the gastric fluid for an extended period of time duringwhich almost the entire medicament contained in the formulation isreleased into the gastric fluid. A disadvantage of the floating system,however, is that it must remain buoyant even while absorbing gastricfluid.

PCT application WO 02/00213 discloses the use of non-hydrated hydrogel,super disintegrant and tannic acid to provide a gastroretentive dosageform of levodopa. The dosage form expands upon contact with gastricfluid to promote its retention in the patient's stomach for a prolongedperiod of time and thereby provide sustained release of the drug.

The retention of the drug in a tablet or other dosage form beyond theduration of the fed mode raises a number of problems that detract fromthe therapeutic efficacy of the drug. These problems arise from thetendency of the tablet to pass from the stomach into the small intestineand reach the colon with the drug still in the tablet. This isespecially problematic when the patient is no longer in the fed mode.This loss of effectiveness is problematic for those drugs that providetheir maximum benefit with minimum side effects when absorbed in thestomach and upper gastrointestinal tract rather than the colon. Thereasons for this site specific effectiveness are either favorablecondition in the stomach, unfavorable conditions in the colon, or both.

To overcome the disadvantages of a gastroretentive dosage form,controlled release dosage forms of carbidopa and levodopa have beenprepared by embedding the active ingredient into a polymer matrix thatslowly erodes to release the active. U.S. Pat. Nos. 4,832,957 and4,900,755 describe controlled release formulations of levodopa/carbidopain which the desired controlled release is achieved by using a polymervehicle that includes a combination of water-soluble and less solublepolymers.

The water soluble polymers in these patents are described as beingselected from hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyvinyl pyrrolidone, polyethylene glycol, starch, and methylcellulose. The less water-soluble polymers are selected from polyvinylacetate-crotonic acid copolymer, polyvinyl chloride, polyethylene,cellulose acetate, polyvinyl alcohol, ethylene vinyl acetate copolymer,polyvinyl acetate, polymethyl methacrylate, ethyl cellulose, and thelike. According to these patents, the preferred polymeric vehicle isdisclosed as being a combination of water-soluble polymer, hydroxypropylcellulose, and the less water soluble polymer polyvinyl acetate-crotonicacid.

Although these patents describe the use of a combination of watersoluble and less water-soluble polymers for preparing a control releaseformulation of carbidopa and levodopa, they do not suggest the use of acombination of different molecular weights of a single cellulose ether.

U.S. Pat. No. 4,389,393 discloses a formulation for the controlledrelease of a medicament by using a polymer vehicle that is a combinationof hydroxypropyl cellulose and hydroxypropyl methylcellulose. However,this patent does not suggest the combination of different molecularweights of a single cellulose ether.

U.S. Pat. No. 6,103,263 describes the use of two types of hydroxypropylcellulose, one of which has a low molecular weight and the other ofwhich has a high molecular weight. The two hydroxypropyl celluloses areused to obtain a pharmaceutical formulation having delayed-pulse,sustained release characteristics over at least 12 hour period. The lowmolecular weight hydroxypropyl cellulose ethers are disclosed as havinga number average molecular weight of 70,000 to 90,000 and the highmolecular weight hydroxypropyl cellulose is disclosed as having a numberaverage molecular weight of 1,100,000 to 1,200,000.

A key disclosure in U.S. Pat. No. 6,103,263 is that the desiredsustained release characteristics of the active ingredient can beensured by a ratio of between 1:1.6 to 1:8.3, and preferably 1:4, of theactive ingredient to the mixture of low molecular weight hydroxypropylcellulose and high molecular weight hydroxypropyl cellulose. It furtherdescribes the ratio of low molecular weight hydroxypropyl cellulose tohigh molecular weight hydroxypropyl cellulose as being from 1:2 to 1:15.The total polymer content amounts to between 24 to 70% by weight of thecomposition.

A disadvantage of this formulation is the increased cost that resultsfrom the higher polymer concentration. Moreover, U.S. Pat. No. 6,103,263does not suggest the use of a combination of low molecular weighthydroxypropyl cellulose and medium molecular weight hydroxypropylcellulose.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a controlled releasepharmaceutical composition that includes carbidopa, levodopa, and acombination of a low molecular weight cellulose ether and a mediummolecular weight cellulose ether. The low molecular weight celluloseether and the medium molecular weight cellulose ether are the same typeof cellulose ether.

Embodiments of the pharmaceutical composition may include one or more ofthe following features. For example, the first and the second celluloseethers may be hydroxypropyl cellulose ethers or hydroxypropyl methylcellulose ethers.

The low molecular weight cellulose ether may be hydroxypropyl celluloseether having a number average molecular weight of between approximately55,000 and approximately 70,000 and, more particularly, approximately65,000. The medium molecular weight cellulose ether may be hydroxypropylcellulose ether having a number average molecular weight of betweenapproximately 110,000 and approximately 150,000 and, more particularly,approximately 125,000.

The ratio of low molecular weight cellulose ether to medium molecularweight cellulose ether may be approximately 0.75:1 to 1.5:1 and, moreparticularly, approximately 1:1. The total cellulose ether concentrationmay be between approximately 2% and approximately 20% w/w of thecomposition.

The controlled release pharmaceutical composition may further includeone or more pharmaceutical excipients. The one or more pharmaceuticalexcipients may be one or more diluents, binders, disintegrants,lubricants, glidants, colorants, and flavoring agents. The controlledrelease pharmaceutical composition may be a tablet.

In another general aspect, there is provided a process for thepreparation of a controlled release composition of carbidopa andlevodopa. The process includes blending carbidopa, levodopa, a lowmolecular weight cellulose ether, and a medium molecular weightcellulose ether, optionally granulating the blend with a binder, andcompressing into a tablet. The first cellulose ether and the secondcellulose ether are the same type of cellulose ether.

Embodiments of the process may include one or more of the followingfeatures. For example, the low molecular weight cellulose ether and themedium molecular weight cellulose ether may be hydroxypropyl celluloseether or hydroxypropyl methyl cellulose ether.

The low molecular weight cellulose ether may be hydroxypropyl celluloseether having a number average molecular weight of between approximately55,000 and approximately 70,000. The medium molecular weight celluloseether may be hydroxypropyl cellulose ether having a number averagemolecular weight of approximately 110,000 to approximately 150,000.

The granules may be prepared by either of a wet granulation or a drygranulation technique. The wet granulation may be performed with one ormore of an aqueous, hydro-alcoholic, or alcoholic dispersion of thebinder.

In another general aspect, there is provided a method of providingdopamine to the brain. The method includes administering a tablet thatincludes carbidopa, levodopa, a low molecular weight cellulose ether,and a medium molecular weight cellulose ether.

Embodiments of the method may include one or more of the followingfeatures. For example, the low molecular weight cellulose ether may behydroxypropyl cellulose ether having a number average molecular weightof between approximately 55,000 and approximately 70,000. The mediummolecular weight cellulose ether may be hydroxypropyl cellulose etherhaving a number average molecular weight of between approximately110,000 and approximately 150,000.

In another general aspect, a method of treating Parkinson's diseaseincludes administering a pharmaceutical composition to a patient in needof treatment for Parkinson's disease. The pharmaceutical compositionadministered includes carbidopa, levodopa, a low molecular weightcellulose ether, and a medium molecular weight cellulose ether. The lowmolecular weight cellulose ether and the medium molecular weightcellulose ether are the same type of cellulose ether.

The low molecular weight cellulose ether may be hydroxypropyl celluloseether having a number average molecular weight of between approximately55,000 and approximately 70,000. The medium molecular weight celluloseether may be hydroxypropyl cellulose ether having a number averagemolecular weight of between approximately 110,000 and approximately150,000.

DETAILED DESCRIPTION OF INVENTION

The inventors have discovered two important characteristics indeveloping a controlled release formulation of carbidopa and levodopa:(1) the formulation can be prepared using a combination of low andmedium molecular weight cellulose ether polymers, such as hydroxypropylcellulose ethers, and (2) the cellulose ether polymers can be providedin a low concentration and yet the formulation produces the desiredrelease profile. The resulting tablet or other dosage form maintainsrelatively steady plasma levodopa levels for four to six hours. Theinventors further found that the use of either low molecular weight ormedium molecular weight hydroxypropyl cellulose without the other didnot give the desired dissolution profile.

The compositions produced by the present process are quite stable andprovide comparable dissolution release profiles when compared to BristolMyers Squibb's Sinemet® CR (the commercially marketed carbidopa/levodopacontrolled release tablets). Because the present process employs lowconcentration of the polymer, the cost of the production is considerablyreduced.

As noted above, the compositions include carbidopa, levodopa, at leasttwo cellulose ethers that are of the same type but one is of a lowmolecular weight and the other is of a medium molecular weight, and oneor more pharmaceutically acceptable excipients or additives. Thecarbidopa may be present in the composition at between approximately 5mg and 300 mg and levodopa may be present at an amount that is betweenapproximately 20 mg and 1200 mg.

The cellulose ethers may be selected from either low and mediummolecular weight hydroxypropyl cellulose ether or hydroxypropyl methylcellulose ether. The low molecular weight hydroxypropyl cellulose may beselected from hydroxypropyl cellulose having a number average molecularweight of between approximately 55,000 and approximately 70,000 and themedium molecular weight hydroxypropyl cellulose may be selected fromhydroxypropyl cellulose having a number average molecular weight ofbetween approximately 110,000 to 150,000. However, the combination ofhydroxypropyl cellulose ether having a number average molecular weightof between about 65,000 and about 125,000 is particularly suitable foreffectively delivering a combination of carbidopa and levodopa.

The concentration of the combination of the low and the medium molecularweight hydroxypropyl cellulose ethers may vary and be as much as 20% oras little as 2% by weight of the total composition. For example, asshown in the examples, it was discovered that one suitable range isbetween 5% and 16% w/w. The ratio of low molecular weight hydroxypropylcellulose to medium molecular weight hydroxypropyl cellulose may varyfrom approximately 0.75:1 to approximately 1.5:1. However, a ratio ofabout 1:1 is preferred.

In addition to the active ingredients and the cellulose ether, theformulation may include pharmaceutically acceptable additives orexcipients, which act in one or more capacities as diluents, binders,disintegrants, lubricants, glidants, colorants or flavoring agents. Forexample, diluents may be selected from lactose, mannitol, sucrose,microcrystalline cellulose, starches, calcium hydrogen phosphate, andother suitable, known diluents. Disintegrants may be selected fromcroscarmellose sodium, crospovidone, sodium starch glycolate, and othersuitable, known disintegrants.

Binders impart cohesiveness to the blend and also improve the flow andhardness. Binders may be selected from excipients, such as starch,sugars, gums, povidone, and other suitable, known binders.

Lubricants may be selected from talc, magnesium stearate, calciumstearate, polyethylene glycol, hydrogenated vegetable oils, stearicacid, sodium lauryl sulphate, sodium stearyl fumarate, sodium benzoate,and other suitable, known lubricants. Glidants may be selected fromcolloidal silicon dioxide, aerosol, talc, and other suitable, knownglidants. Suitable coloring and flavoring agents include those approvedfor use by the United States Food and Drug Administration (FDA) and arewell known to those skilled in the art.

The formulation may be prepared by dry blending levodopa and carbidopawith a combination of low molecular weight hydroxypropyl cellulose andmedium molecular weight hydroxypropyl cellulose, wet granulating theblend with an aqueous solution of binder, drying and sizing the wetgranules, and compressing the granules. Although wet granulation worksvery well in forming the dosage forms, direct compression and drygranulation techniques may instead be used to prepare tablets. Thetablets can be optionally coated using any standard coating process.

The following examples are provided to enable one of ordinary skill inthe art to prepare dosage forms of the invention and should not beconstrued as limiting the scope of the invention. In the followingexamples, the carbidopa/levodopa tablets were prepared using the polymerbeing present at between approximately 2% and approximately 20% w/w ofthe total composition.

EXAMPLES 1-8

Weight (mg per tablet) Ingredient 1 2 3 4 5 6 7 8 Carbidopa 54.91 59.2854.91 54.91 54.91 54.91 54.39 54.94 Levodopa 201.35 201.35 201.35 201.35201.35 201.35 201.73 201.73 Microcrystalline 50.515 26.35 5.04 8.0410.04 20.04 12.88 9.64 cellulose HPC-L* 15.0 25.0 15 15 12.5 7.5 12.512.5 HPC-M** 20.0 30.0 15 12 12.5 7.5 10 12.5 Povidone K-30 3.5 3.5 3 33 3 3 3 Iron oxide red 0.35 0.35 0.2 0.2 0.2 0.2 0.25 0.3 D & C yellow0.875 0.875 0.5 0.5 0.5 0.5 0.25 0.4 no. 10 Granulating q.s. q.s. q.sq.s q.s q.s q.s q.s fluid*** Magnesium 3.5 3.5 5 5 5 5 5 5 stearate*HPC-L = Low molecular weight hydroxypropyl cellulose,**HPC-M = Medium molecular weight hydroxypropyl cellulose,***Granulating fluid = Water, alcohol or mixture of bothProcess:

-   1. Each of the ingredients was sieved to the appropriate size and    the required amount of each ingredient was weighed out.-   2. A solution of povidone was prepared in granulating fluid.-   3. Carbidopa, levodopa, hydroxypropyl cellulose, microcrystalline    cellulose, and colorants were blended.-   4. The blend of step 3 was granulated using the povidone solution of    step 2 and the resulting granules were dried and sized.-   5. The sized granules of step 4 were lubricated with magnesium    stearate and compressed into suitable sized tablets.

Table 1 provides comparative dissolution data for the marketed Sinemet®CR and the controlled release tablets of carbidopa/levodopa of examples1-8. The testing was performed in 0.1N HCl (900 ml), USP 2 at 50 rpm. Asindicated below in Table 1, the controlled release tablets preparedaccording to the above examples provide a sustained release of carbidopaand levodopa for at least 2.5 hours. The dissolution profile clearlyshows that a 0.75:1-1.5:1 ratio of low to medium molecular weighthydroxypropyl cellulose provides an extended release profile that issimilar to that of Sinemet® CR. Moreover, the desired release ofcarbidopa and levodopa can be achieved using a low concentration ofhydroxypropyl cellulose. TABLE 1 Comparative dissolution of thecontrolled release tablets of Carbidopa levodopa prepared as perExamples 1-8 and Sinemet ® CR in 0.1N HCl (900 ml), USP 2 at 50 rpm. %drug released Sinemet ® Time Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7Ex. 8 CR (h) C L C L C L C L C L C L C L C L C L 0.5 36 35 27 26 36 3837 38 31 31 29 34 33 35 31 34 33 35 1.0 68 66 50 48 54 57 60 63 53 52 5455 65 69 57 59 59 61 1.5 89 87 74 70 75 79 78 81 — — — — — — — — — — 2.0101 99 91 86 87 92 87 92 — — — — — — — — — — 2.5 107 106 104 97 98 10395 100 98 96 97 95 103 108 93 96 97 98C—CarbidopaL—Levodopa

EXAMPLES 9-10

Weight (mg per tablet) Ingredient 9 10 Carbidopa 25.0 50.0 Levodopa100.0 200.0 Microcrystalline cellulose 6.226 12.452 HPC-L* 6.25 12.5HPC-M** 6.25 12.5 Povidone K-30 1.5 3.0 Iron oxide red 0.1250 0.25 Ironoxide yellow 0.1250 0.25 Granulating fluid*** q.s. q.s. Magnesiumstearate 2.5 5.0*HPC-L = Low molecular weight hydroxypropyl cellulose,**HPC-M = Medium molecular weight hydroxypropyl cellulose,***Granulating fluid = Water, alcohol or mixture of bothProcess:

-   1. Each of the ingredients was sieved to the appropriate size and    the required amount of each ingredient was weighed out.-   2. A solution of povidone was prepared in granulating fluid.-   3. Carbidopa, levodopa, hydroxypropyl cellulose, microcrystalline    cellulose and part of the colorants were blended.-   4. The blend of step 3 was granulated using the povidone solution of    step 2, dried, and sized.-   5. The sized granules of step 4 were blended with the remaining    amount of colorants, lubricated with magnesium stearate, and    compressed into suitably sized tablets.

Table 2 provides comparative dissolution data for the marketed Sinemet®CR and the controlled release tablets of carbidopa/levodopa of Examples9 and 10. The testing was performed in 0.1N HCl (900 ml), USP 2 at 50rpm. The controlled release tablets prepared according to Examples 9 and10 provide controlled release of carbidopa and levodopa for 4 hours. Thedissolution profile clearly shows that a 0.75:1-1.5:1 ratio of low tomedium molecular weight hydroxypropyl cellulose provides an extendedrelease profile that is similar to that of Sinemet® CR. Moreover, thedesired release of carbidopa and levodopa can be achieved using a lowconcentration of hydroxypropyl cellulose. TABLE 2 Comparativedissolution of the controlled release tablets of carbidopa and levodopaprepared as per Examples 9-10 and Sinemet ® CR in 0.1N HCl (900 ml), USP2 at 50 rpm. % drug released Sinemet ® CR Ex. 9 Ex. 10 Batch 1 Batch 2Time (h) C L C L C L C L 0.5 36 38 29 29 36 39 36 36 1.0 59 61 50 50 5759 58 59 2.5 96 99 89 89 92 95 97 100 4.0 100 103 104 105 97 99 100 104C—CarbidopaL—Levodopa

The compositions and tablets described above can be administered topatients in need of increased dopamine levels in the brain e.g.,patients suffering from Parkinson's disease. By administering thecomposition in the form of tablets or other dosage form, the patient isultimately provided with dopamine to the brain.

While several particular forms of the invention have been illustratedand described, it will be apparent that various modifications andcombinations of the invention detailed in the text can be made withoutdeparting from the spirit and scope of the invention. For example, a lowmolecular weight and a medium molecular weight hydroxypropyl methylcellulose ether can be used in the composition in place of thehydroxypropyl cellulose ethers. Further, it is contemplated that anysingle feature or any combination of optional features of the inventivevariations described herein may be specifically excluded from theclaimed invention and be so described as a negative limitation.Accordingly, it is not intended that the invention be limited, except asby the appended claims.

1. A controlled release pharmaceutical composition, the compositioncomprising carbidopa, levodopa, and a combination of a low molecularweight cellulose ether and a medium molecular weight cellulose ether,wherein the low molecular weight cellulose ether and the mediummolecular weight cellulose ether are the same type of cellulose ether.2. The controlled release pharmaceutical composition of claim 1, whereinthe low molecular weight cellulose ether and the medium molecular weightcellulose ether comprise hydroxypropyl cellulose ether.
 3. Thecontrolled release pharmaceutical composition of claim 1, wherein thelow molecular weight cellulose ether and the medium molecular weightcellulose ether comprise hydroxypropyl methyl cellulose ether.
 4. Thecontrolled release pharmaceutical composition of claim 1, wherein thelow molecular weight cellulose ether comprises hydroxypropyl celluloseether having a number average molecular weight of between approximately55,000 and approximately 70,000.
 5. The controlled releasepharmaceutical composition of claim 4, wherein the low molecular weighthydroxypropyl cellulose has a number average molecular weight ofapproximately 65,000.
 6. The controlled release pharmaceuticalcomposition of claim 1, wherein the medium molecular weight celluloseether comprises hydroxypropyl cellulose ether having a number averagemolecular weight of between approximately 110,000 and approximately150,000.
 7. The controlled release pharmaceutical composition of claim6, wherein the medium molecular weight hydroxypropyl cellulose has anumber average molecular weight of approximately 125,000.
 8. Thecontrolled release pharmaceutical composition of claim 1, wherein aratio of low molecular weight cellulose ether to medium molecular weightcellulose ether is approximately 0.75:1 to 1.5:1.
 9. The controlledrelease pharmaceutical composition of claim 1, wherein a ratio of lowmolecular weight cellulose ether to medium molecular weight celluloseether is approximately 1:1.
 10. The controlled release pharmaceuticalcomposition of claim 1, wherein the total cellulose ether concentrationis between approximately 2% and approximately 20% w/w of thecomposition.
 11. The controlled release pharmaceutical composition ofclaim 1, wherein the pharmaceutical composition comprises a tablet. 12.The controlled release pharmaceutical composition of claim 1, furthercomprising one or more pharmaceutical excipients.
 13. The controlledrelease pharmaceutical composition of claim 12, wherein the one or morepharmaceutical excipients comprise one or more diluents, binders,disintegrants, lubricants, glidants, colorants, and flavoring agents.14. A process for the preparation of a controlled release composition ofcarbidopa and levodopa, the process comprising: blending carbidopa,levodopa, a low molecular weight cellulose ether, and a medium molecularweight cellulose ether; optionally granulating the blend with a binder;and compressing into a tablet, wherein the low molecular weightcellulose ether and the medium molecular weight cellulose ether are thesame type of cellulose ether.
 15. The process of claim 14, furthercomprising blending with one or more pharmaceutically acceptableexcipients.
 16. The process of claim 14, wherein the low molecularweight cellulose ether and the medium molecular weight cellulose ethercomprise hydroxypropyl cellulose ether.
 17. The process of claim 14,wherein the low molecular weight cellulose ether comprises hydroxypropylcellulose ether having a number average molecular weight of betweenapproximately 55,000 and approximately 70,000.
 18. The process of claim14, wherein the medium molecular weight cellulose ether compriseshydroxypropyl cellulose ether having a number average molecular weightof approximately 110,000 to approximately 150,000.
 19. The process ofclaim 14, wherein granulating comprises one of a wet granulation or adry granulation technique.
 20. The process of claim 19, wherein the wetgranulation is done with one or more of an aqueous, hydro-alcoholic, oralcoholic dispersion of the binder.
 21. A method of providing dopamineto the brain, the method comprising administering a tablet comprisingcarbidopa, levodopa, a low molecular weight cellulose ether, and amedium molecular weight cellulose ether, wherein the low molecularweight cellulose ether and the medium molecular weight cellulose etherare the same type of a cellulose ether.
 22. The method of claim 21,wherein the low molecular weight cellulose ether comprises hydroxypropylcellulose ether having a number average molecular weight of betweenapproximately 55,000 and approximately 70,000.
 23. The method of claim21, wherein the medium molecular weight cellulose ether compriseshydroxypropyl cellulose ether having a number average molecular weightof approximately 110,000 to approximately 150,000.
 24. A method oftreating Parkinson's disease, the method comprising administering apharmaceutical composition to a patient in need of treatment forParkinson's disease, the pharmaceutical composition comprisingcarbidopa, levodopa, a low molecular weight cellulose ether, and amedium molecular weight cellulose ether, wherein the low molecularweight cellulose ether and the medium molecular weight cellulose etherare the same type of cellulose ether.
 25. The method of claim 24,wherein the low molecular weight cellulose ether comprises hydroxypropylcellulose ether having a number average molecular weight of betweenapproximately 55,000 and approximately 70,000.
 26. The method of claim24, wherein the medium molecular weight cellulose ether compriseshydroxypropyl cellulose ether having a number average molecular weightof approximately 110,000 to approximately 150,000.